Abstract Hospitalizations for disease, injury, and/or surgery in older adults are likely to impair physical mobility and, therefore, the older adults capacity to be physically active both during hospitalization and beyond. The resulting sedentary lifestyle is likely to be accepted as the new normal, ultimately increasing the risk of skeletal muscle dysfunction (e.g. sarcopenia). Muscle atrophy and loss in strength is an unfortunate consequence with disuse in older adults. We have observed with our bed rest studies in healthy older adults that in addition to muscle and strength changes, there is a substantial increase in skeletal muscle inflammation and an upregulation of enzymes related to de novo ceramide biosynthesis. The accumulation of local inflammation and ceramide, a toxic lipid intermediate, can impair muscle growth. Metformin treatment may attenuate muscle loss by blunting inflammatory pathways and ceramide accumulation. Though metformin has traditionally served as an insulin sensitizer, its use as a preventive strategy to maintain muscle health during a period of physical inactivity in older adults has not been investigated. Therefore, we have proposed to conduct a clinical study in older adults to test whether metformin treatment during bed rest will attenuate muscle atrophy, weakness and muscle inflammatory mechanisms. These findings will be foundational in the development of novel treatments, such as metformin, to prevent muscle dysfunction in older adults during disuse periods.!